The neurodegenerative diseases affect progressively the brain function and more generally the nervous system. The process involved consists generally in a deterioration of the functioning of the nervous cells, in particular the neurons, leading to the cellular death. The consequence for the patient is a progressive alteration, usually irreversible, of the nervous functions which can induce his death. The clinical outcome can be either some damages of the psychic function, leading to dementia such as in Alzheimer's or Pick's disease, or motor abnormalities such as in amyotrophic lateral sclerosis or Parkinson's disease, or the combination of both such in Huntington's chorea disease or Creutzfeldt-Jacob's disease.
Alzheimer's disease (AD) is the most known and spread of the neurodegenerative diseases. It is characterized by memory loss and sometimes by disorders of reasoning, organization, language and perception. It is widely admitted that the AD symptoms arise from an increase of the production or accumulation of a specific protein (β-amyloid) in the brain, which leads to the death of nervous cell. Increasing age is the greatest know risk factor for AD. Approximately 30 millions of people in the world are affected by AD. Population ageing suggests that the economic burden caused by AD disease will become increasingly important.
Parkinson's disease (PD) is the second most common neurodegenerative disorder in the United States and approximately 1-2% of worldwide population older than 65 years suffers from this progressive disease (Dorsey E R. et al. Neurology 2007; 68: 384). The predominant motor symptoms of PD including slow movement, resting tremor, rigidity and gait disturbance are caused by the loss of dopaminergic neurons in the substantia nigra. Although the etiology of PD remains so far unknown, both genetic and environmental factors appear to play a role (Paisan-Ruiz C. et al. Neuron. 2004; 44: 595 and Vila M. and Przedborski S. Nat. Med. 2004; Suppl 10: S58).
Huntington's disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disease that affects approx. 30,000 individuals in the US (about 200,000 individuals are at risk) (Harper P S. Hum. Genet. 1992; 89: 365). HD is clinically characterized by abnormal involuntary movements, behavioral disturbance, cognitive dysfunction and psychiatric disease. Massive loss of GABAergic medium spiny neurons (MSNs) of the striatum occurs in the HD brain together with enlargement of the ventricles and a corresponding shrinkage of the overlying cortex. MSNs of the striatum project into various regions of the CNS and are the key drivers of the progression of degenerative process that involves the remainder of the basal ganglia and subsequent dissemination including cortex and substantia nigra (Andric J. et al. Neurosci. Lett. 2007; 416: 272 and Frank S et al. Neurology. 2004; 62: A204). Dopamine, glutamate and γ-aminobutiric acid (GABA) are thought to be the most affected neurotransmitters in HD (Gunawardena S. et al. Arch. Neurol. 2005; 62: 46).
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective motor neuron death. Both upper motor neurons in the motor neuron cortex and lower motor neurons in the brainstem and in the ventral horn of the spinal cord are affected. Patients develop a progressive muscle phenotype characterized by spasticity, hyperreflexia, fasciculations, muscle atrophy and paralysis. ALS is usually lethal within 3 to 5 years after diagnosis, only 5-10% of patients survive beyond 10 years. There are approximately 140,000 new cases diagnosed worldwide each year. In most cases (90%) there is no family history of ALS. However a clear family history is present in 10% of patients who then suffer from familial ALS. Although the familial ALS is in almost all cases inherited in an autosomal dominant way, autosomal recessive and X-linked forms exist. Mutations in more than 10 different genes are known to cause familial ALS. Many mechanisms have been suggested to play a role in the pathogenesis and disease progression. These include amongst others neuronal excitotoxicity, mitochondrial dysfunction, deregulated autophagy, axonal transport dysfunction and refraction (Cudkowicz M E Ann. Neurol. 1997 41, 210-221).
Albeit, there is currently no treatment leading to the AD recovery, there are 2 types of drugs which can decrease its symptoms and slow down its evolution. EP236684A, DE 3805744A and EP296560A disclose drugs based on acetylcholinesterase inhibitors: galantamine, rivastigmine and donepezil respectively. EP392059A discloses a drug containing memantine which is a NMDA receptor antagonist. All these drugs have received a marketing authorization to treat AD. However, the treatment only affects the symptoms. Several studies have shown that these drugs slow down only in a modest way the progression of cognitive symptoms as well as erratic behaviors in some patients. Moreover, half of the patients who received these drugs do not respond to these treatments. Finally, these drugs induce several undesirable effects such as nausea, diarrhea, hepatic disorders etc. . . . . Thus, there is an urgent need for drugs with a new mechanism of action different from the aforementioned drugs. Several projects are being explored currently. Few examples are mentioned hereafter.
The secretase inhibitors block the transformation process of the β-amyloid protein precursor (known as “APP”) into the β-amyloid protein and thus permit to slow down its dangerous accumulation in the brain. Among these inhibitors is the tramiprosate (ALZHEMED®) which was tested in a phase II clinical study (Aisen P S et al. Neurology 2006; 28: 1757). Another inhibitor, the scillo-cyclohexanehexol, was tested in animals successfully (MacLarin J A et al. Nat. Med. 2006; 12: 801). These molecules interact with β-amyloid proteins during their formation and prevent them from agglomerating and from forming small aggregates, which destroy nervous cells by settling as solid plaques. However, they already cause important damage during their formation.
Other treatments such as ubiquitin (compound naturally produced in the brain) induce the disappearance of β-amyloid protein before its reaches high accumulation in the brain (Taddei N. et al. Neurosci. Lett. 1993; 151: 158). However, the ubiquitin rates remain insufficient in patients which suffer from Alzheimer's disease.
Another interesting method is the immunological approach. WO 94/06476A discloses a new type of drug which has a target different from the molecules cited previously: Etanercept (ENBREL®), which is a fusion protein directed against the TNF-α pro-inflammatory cytokine A recent pilot study was carried out over a 6 months period and showed encouraging results in term of cognitive improvement (Tobinick E. CNS Drugs 2009; 23: 713). In addition to the fact that the project is at a preliminary phase at the clinical level, the administration of the product ENBREL® was carried out by perispinal route in order to circumvent the problem linked to its incapacity to pass across the blood-brain barrier (BBB) (Griffin S. Newspaper of Neuroinflammation; 2008; 5: 3). However, this route of administration is burdensome and painful for the patient and requires a certain number of precautions: it must be carried out in hospitals. The presence of the blood-brain barrier (BBB) restricts strongly the passage of molecules such as ENBREL® from the plasma into the cerebral extracellular medium: very few drugs designed in laboratories, cross this barrier to treat brain diseases.
Limited therapeutic options are available to PD, HD and ALS patients as only symptomatic treatments have received marketing authorizations so far. The major challenge for clinical development of new drug entities in neurodegenerative disorders lies in the difficulty to identify and hit disease-relevant targets that will beneficially interfere with complex physiopathological mechanisms. Moreover such therapeutic agent must cross the BBB and reach diseased regions of the central nervous system. U.S. Pat. Nos. 4,900,755 and 6,238,699 disclose an oral formulation for the controlled release of the combination of levodopa/carbidopa (SINEMET®). This treatment compensates for the loss of dopaminergic neurons that occurs in PD brains. Carbidopa, a decarboxylase inhibitor, prevents peripheral metabolism of levodopa, the precursor of dopamine, outside of the brain. In the brain levodopa is broken down into dopamine which increases dopamine concentration in the striatum. Levodopa, dopamine precursor is used because the natural neurotransmitter does not cross the BBB. Tetrabenazine (XENAZINE®) is an oral dopamine-depleting agent that treats chorea associated with HD. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor. It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles (Guay D. Am. J. Geriatr. Pharmacother. 2010; 8: 331). Finally, riluzole (RILUTEK®) is the only approved treatment for ALS which increases lifespan by only 2-3 months after 1.5 years of treatment, and is effective at delaying the use of assisted mechanical ventilation in bulbar patients (Miller R G et al. Neurology 2009; 73: 1218 and Bellingham M C. CNS Neurosci. Ther. 2011; 17: 4). Pharmacological properties of riluzole include an inhibitory effect on glutamate release mediated by inactivation of voltage-dependent sodium channels and by its ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors. Although these drugs reduce cognitive or motor symptoms and improve quality of life, they fail to modify or halt disease progression. Their long-term use is associated with side-effects that often require treatment arrest.
Therefore, there is a need for drugs which should at the one hand be sufficiently effective to treat AD, PD, HD or ALS and on the other hand cross the BBB. The Applicant objective is to develop a drug capable to treat of Alzheimer's disease and other neurodegenerative disorders without presenting the disadvantages of the existing treatments. The Applicant has found, in a fortuitous way, due to the work already carried out with this molecule, that a peptide analog of thymulin hormone has an interesting potential in the prevention and the treatment of AD, PD, HD and ALS.
We know since the late 1950's the central role played by the thymus in the differentiation of T-cells, responsible in particular of transplant rejection and implicated in the immune defense against the viruses and some bacteria. The hormone secreted by the thymus was then identified as a peptide of 9 amino-acids: the thymulin (Pleau J M et al. Immunol. Lett, 1979; 1:179; Amor et al, Annals Rheum. Dis. 1987; 46: 549). The thymulin effects on the immune system were shown to be zinc-dependent. Indeed, zinc confers to the thymulin a tetrahedral conformation which corresponds to the active form of the molecule. In the absence of zinc, thymulin is no longer active on the immune system. Work was undertaken specifically on a nonapeptide called “PAT” having the sequence of amino-acids Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asp (EAKSQGGSD). The application WO 03/030927A reports that several derivatives of thymulin, such as the PAT nonapeptide presents analgesic and anti-inflammatory properties, and can treat in pain including neurogenic pain. More recently, the application WO 2009/150310A describes specifically the use of the PAT nonapeptide in the treatment of autoimmune diseases such as rheumatoid arthritis, and intestinal bowel diseases (IBD) such as Crohn's disease and hemorrhagic rectocolitis.